Pharmaceutical formulation of N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-YL]-4-[(3R,5S)-3 ,5-dimethylpiperazin-1-YL] benzamide

ABSTRACT

There are provided pharmaceutical compositions comprising a compound of Formula (I) as defined herein and an amount of an alkaline effervescent agent that is sufficient to provide satisfactory in vitro dissolution; and further comprising one or more pharmaceutically acceptable ingredients; and to processes for obtaining them.

This application is a continuation of U.S. application Ser. No.14/108,595, filed on Dec. 17, 2013, which claims the benefit under 35U.S.C. § 119(e) of Application No. U.S. 61/740,520 filed on 21 Dec.2012.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical/formulation chemistry.The invention is understood to apply generally to formulations ofcompounds which contain an increased percent loading of the activeingredient. As a preferred aspect, provided herein are formulations ofN-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide(Compound I) which exhibit satisfactory manufacturability, stability andin vitro dissolution. The formulations are useful for treating ofcancer.

BACKGROUND OF THE INVENTION

In the manufacture of pharmaceutical formulations for oraladministration, it may be desirable for the drug to dissolve rapidlysoon after administration. However, it is known that certainphysic-chemical properties of the drug, such as particle size,wettability, or solubility, may lead to a pharmaceutical formulationwhich exhibits unsatisfactory and/or variable dissolution or to aformulation which exhibits unsatisfactory and/or variablebioavailability. Such formulations may be unsuitable for use bypatients.

Compound I (below) is disclosed in international patent application

for use in the treatment of cancer.

Javaid et al (J. Pharm. Sci. 61 (9) 1972 pp 1370-1373) studied theeffect of various classes of buffering agents on the dissolution ofaspirin from tablet formulations. Compound I is currently in clinicalstudies for the treatment of cancer, in particular cancers of the lung,breast, gatric and bladder. Dosing is currently done with orallydelivered tablets with tablet strengths of 20 and 100 mg. These tabletsexhibit satisfactory dissolution across the physiological pH range.However, the manufacturing process used for clinical batches cannot beoperated at commercial scale, due to a high incidence of filming whichcannot be corrected using conventional means. It is desirable,therefore, to produce new pharmaceutical formulations of Compound Iwhich overcome at least in part the above problems.

DESCRIPTION OF THE INVENTION

This invention is generally directed to formulations of compounds withimproved manufacturability, in particular to formulations which containan alkaline effervescent excipient and which exhibit satisfactorydissolution across the physiological pH range.

The compound of formula (I) (known hereafter as “Formula (I)”) is shownbelow:

The compound of Formula (I) is a base and exhibits pH dependentsolubility, having a solubility in simulated gastric fluid (pH 1.2) ofapproximately 5 mg/mL (‘slightly soluble’, using the definition given inthe United States Pharmacopeia/National Formulary, USP35-NF30), whichreduces in fasted simulated intestinal fluid (pH 6.5) to approximately0.25 mg/mL (‘very slightly soluble’ by the USP definition). Furthermore,we have observed that the compound of Formula (I) may form a viscousmaterial at low pH, which has the effect of reducing the rate at whichthe drag dissolves. In order to achieve an acceptable rate and extent ofdissolution across the physiological pH range, the earlier clinicalformulation was manufactured using conditions designed to give a finegranule which, when compressed into tablet form would disperse rapidlyupon administration. While this approach did result in an improvement indissolution performance, ‘filming’ problems were experienced duringmanufacture. In addition, it was observed that the use of conventionallubricants such as magnesium stearate and sodium stearyl fumarate led tochemical degradation including impurity formation and/or complexation.

It was unexpectedly found that alkaline effervescent excipients wereeffective in both improving the rate and extent of dissolution at lowpH, despite the reduction in solubility under alkaline conditions, andin ameliorating the “filming” issues. A further unexpected finding wasthat the use of an alternative lubricant, glyceryl dibehenale, waseffective in ameliorating chemical degradation.

In particular, this invention is directed at least in part to theunexpected result that the use of an alkaline effervescent excipientwith Formula (I) in the formulation allows the manufacture of tabletswith improved manufacturability and/or a satisfactory dissolution acrossthe physiological pH range; and, at least in part, to the unexpectedresult that an alternative lubricant allows the manufacture of tabletswith improved stability.

In a further aspect, this invention provides the use of an alkalineeffervescent excipient with Formula (I) in the formulation allowing themanufacture of tablets with improved manufacturability and/or asatisfactory dissolution across the physiological pH range.

In a still further aspect, this invention provides the use of magnesiumcarbonate with Formula (I) in the formulation allowing the manufactureof tablets with improved manufacturability and/or a satisfactorydissolution across the physiological pH range. In a still furtheraspect, this invention provides the use of calcium carbonate withFormula (I) in the formulation allowing the manufacture of tablets withimproved manufacturability and/or a satisfactory dissolution across thephysiological pH range.

In a still further aspect, this invention provides the use of sodiumbicarbonate with Formula (I) in the formulation allowing the manufactureof tablets with improved manufacturability and/or a satisfactorydissolution across the physiological pH range.

In a further aspect, this invention provides the use of an alternativelubricant with Formula (I) in the formulation allowing the manufactureof tablets with improved stability.

In a still further aspect, this invention provides the use of glyceryldibehenate with Formula (I) in the formulation allowing the manufactureof tablets with improved stability.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising greater than 10% w/w of Formula (I) and an amountof an alkaline effervescent excipient that is sufficient to providesatisfactory in vitro dissolution; and further comprising one or morepharmaceutically acceptable ingredients.

In another aspect of the invention, there is provided a pharmaceuticalcomposition in unit dosage form comprising from 10 mg to 200 mg ofFormula (I) (for example 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170mg, 180 mg, 190 mg or 200 mg) and an amount of an alkaline effervescentexcipient that is sufficient to provide satisfactory in vitrodissolution; and further comprising one or more pharmaceuticallyacceptable ingredients. For the avoidance of doubt, each of the previousintegers represents a separate and independent aspect of the invention.

In another aspect of the invention a unit dosage form of thepharmaceutical composition comprises between about 10 mg to about 160 mgof Formula (I).

In another aspect of the invention a unit dosage form of thepharmaceutical composition comprises between about 10 mg to about 140 mgof Formula (I).

In a still further aspect, a unit dosage form of the pharmaceuticalcomposition comprises between about 10 mg to about 130 mg of Formula(I).

In a yet further aspect, a unit dosage form of the pharmaceuticalcomposition comprises between about 15 mg to about 110 mg of Formula(I).

In a specific aspect of the invention, a unit dosage form of thepharmaceutical composition comprises 20 mg±1 mg of Formula (I).

In a further specific aspect of the invention, a unit dosage form of thepharmaceutical composition comprises 80 mg±4 mg of Formula (I).

In a further specific aspect of the invention, a unit dosage form of thepharmaceutical composition comprises 100 mg±5 mg of Formula (I).

In a further specific aspect of the invention, a unit dosage form of thepharmaceutical composition comprises 160 mg±8 mg of Formula (I).

In a further specific aspect of the invention, a unit dosage form of thepharmaceutical composition comprises 200 mg±10 mg of Formula (I).

In another aspect of the invention the pharmaceutical compositioncomprises between 10% w/w to 60% w/w of Formula (I).

In a further aspect, the pharmaceutical composition comprises between15% w/w to 50% w/w of Formula (I).

In a still further aspect, the pharmaceutical composition comprisesbetween 15% w/w to 45% w/w of Formula (I).

In a still further aspect, the pharmaceutical composition comprisesbetween 15% w/w to 40% w/w of Formula (I).

In a still further aspect, the pharmaceutical composition comprisesbetween 15% w/w to 25% w/w of Formula (I).

In another aspect of the invention the pharmaceutical compositioncomprises about 20% w/w of Formula (I).

In a specific aspect of the invention, the pharmaceutical compositioncomprises 21.33%±5% w/w of Formula (I).

In a further aspect, the pharmaceutical composition comprises between20.26% w/w to 22.40% w/w of Formula (I).

In a still further aspect of the invention, the pharmaceuticalcomposition comprises from 1% w/w to 50% w/w of an alkaline effervescentexcipient

In a still further aspect of the invention, the pharmaceuticalcomposition comprises from 1% w/w to 40% w/w of an alkaline effervescentexcipient

In a further aspect, the pharmaceutical composition comprises from 10%w/w to, 30% w/w of an alkaline effervescent excipients.

In a still further aspect, the pharmaceutical composition comprisesabout 20% w/w of an alkaline effervescent excipients.

In a further aspect, the pharmaceutical composition comprises from 15%w/w to 20% w/w of an alkaline effervescent excipients.

In a still further aspect of the invention, the pharmaceuticalcomposition comprises less than or equal to 6% w/w of a conventionallubricant

Alternatively the use of an alternative lubricant may improve stability.

In a still further aspect of the invention, the pharmaceuticalcomposition comprises less than or equal to 5% w/w of an alternativelubricant

In a still further aspect of the invention, the pharmaceuticalcomposition comprises less than or equal to 4% w/w of an alternativelubricant

In a further aspect, the pharmaceutical composition comprises less thanor equal to 3% w/w of an alternative lubricant.

In a still further aspect of the invention, the pharmaceuticalcomposition comprises between 0.25% w/w and 8% w/w of an alternativelubricant.

In a still further aspect of the invention, the pharmaceuticalcomposition comprises between 0.5% w/w and 5% w/w of an alternativelubricant.

In a still further aspect of the invention, the pharmaceuticalcomposition comprises between 1% w/w and 4% w/w of an alternativelubricant.

In a still further aspect of the invention, the pharmaceuticalcomposition comprises between 2.5% w/w and 3.5% w/w of an alternativelubricant.

In a further aspect, the pharmaceutical composition comprises about 3%w/w of an alternative lubricant.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising greater than 10% w/w of Formula (I) and less thanor equal to 50% w/w of an alkaline effervescent excipient; and furthercomprising one or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising greater than 15% w/w of Formula (I) and less thanor equal to 40% w/w of an alkaline effervescent excipient; and furthercomprising one or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising greater than 15% w/w of Formula (I) and less thanor equal to 30% w/w of an alkaline effervescent excipient; and furthercomprising one or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising greater than 15% w/w of Formula (I) and less thanor equal to 20% w/w of an alkaline effervescent excipient; and furthercomprising one or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising from 10% w/w to 50% w/w of Formula (I) and from1% w/w to 50% w/w of an alkaline effervescent excipient; and optionallyfurther comprising one or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising from 15% w/w to 35% w/w of Formula (I) and from10% to 40% w/w of an alkaline effervescent excipient; and furthercomprising one or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising from 15% w/w to 25% w/w of Formula (I) and from15% w/w to 25% w/w of an alkaline effervescent excipient; and furthercomprising one or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising about 20% w/w of Formula (I) and about 20% w/w ofan alkaline effervescent excipient; and further comprising one or morepharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a unit dosageform comprising from 15% w/w to 45% w/w of Formula (I) and from 10% to40% w/w of an alkaline effervescent excipients and further comprisingone or more pharmaceutically acceptable ingredients, wherein the unitcomprises from 10 to 200 mg of Formula (I)

In a further aspect of the invention, there is provided a unit dosageform comprising from 15% w/w to 40% w/w of Formula (I) and from 10% to40% w/w of an alkaline effervescent excipients and further comprisingone or more pharmaceutically acceptable ingredients, wherein the unitcomprises from 10 to 200 mg of Formula (I).

In a further aspect of the invention, there is provided a unit dosageform comprising from 15% w/w to 25% w/w of Formula (I) and from 15% to25% w/w of an alkaline effervescent excipients and further comprisingone or more pharmaceutically acceptable ingredients, wherein the unitcomprises 20 mg of Formula (I).

In a further aspect of the invention, there is provided a unit dosageform comprising from 15% w/w to 25% w/w of Formula (I) and from 15% to25% w/w of an alkaline effervescent excipients and further comprisingone or more pharmaceutically acceptable ingredients, wherein the unitcomprises 80 mg of Formula (I).

In a further aspect of the invention, there is provided a unit dosageform comprising from 15% w/w to 25% w/w of Formula (I) and from 15% to25% w/w of an alkaline effervescent excipients and further comprisingone or more pharmaceutically acceptable ingredients, wherein the unitcomprises 160 mg of Formula (I).

In a further aspect of the invention, optional ingredients which can beadded to the pharmaceutical composition include one or more of thefollowing:

a) fillers;

b) binding agents;

c) lubricants; and

d) disintegrants.

Where optional ingredients are added to make up the remainder of thepharmaceutical composition, the remainder may optionally include one ormore of the following:

-   -   a) fillers which, when employed, range between for example about        10 to about 75 weight percent (e.g. about 15 to about 70 weight        percent) of the remainder of the dry formulation;    -   b) binding agents which, when employed range between for example        about 2 to about 8 weight percent of the remainder of the dry        formulation;    -   c) lubricants which, when employed, range from between about        0.25 and 5 weight percent of the remainder of the dry        formulation; and    -   d) disintegrants which, when employed, range from between about        0.5 and 10.0 weight percent (e.g. about 5 weight percent) of the        remainder of the dry formulation.

In a further aspect of the invention, the pharmaceutical compositionfurther comprises one or more additional ingredients independentlyselected from, for example

a) fillers such as mannitol (e.g. Pearlitol 50c, Peralitol 120c orPearlitol 160c) or microcrystalline celluloses (e.g. MCC Avicel PH 101,Emcocel 90M, etc.);

b) binding agents such as Plasdone K29/32, Povidone, microcrystallinecelluloses or Kollidon K30;

c) lubricants such as glyceryl dibehenate; and

d) disintegrants such as sodium starch glycolate, for example ExploTabor Glycolys LV.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising from 15% w/w to 25% w/w of Formula (I), from 15%w/w to 25% w/w of an alkaline effervescent excipients, from 2.5% w/w to3.5% w/w of an alternative lubricant; and further comprising from 40%w/w to 60% filler w/w, from 1% w/w to 3% w/w binder and 5% w/w to 9% w/wdisintegrant.

In another aspect of the invention, there is provided a tabletcomprising greater than 10% w/w of Formula (I) and an amount of analkaline effervescent excipient that is sufficient to providesatisfactory in vitro dissolution; and further comprising one or morepharmaceutically acceptable ingredients.

In another aspect of the invention, there is provided a tabletcomprising from 10 mg to 200 mg of Formula (I) (for example 20 mg, 30mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg,130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg 190 mg or 200 mg) and anamount of an alkaline effervescent excipient that is sufficient to aprovide satisfactory in vitro dissolution; and further comprising one ormore pharmaceutically acceptable ingredients. For the avoidance ofdoubt, each of the previous integers represents a separate andindependent aspect of the invention.

In another aspect of the invention, the tablet comprises between about10 mg to about 160 mg of Formula (I).

In another aspect of the invention the tablet comprises between about 10mg to about 140 mg of Formula (I).

In a still further aspect, the tablet comprises between about 10 mg toabout 130 mg of Formula (I).

In a still further aspect, the tablet comprises between about 15 mg toabout 110 mg of Formula (I).

In a specific aspect of the invention, the tablet comprises 20 mg±1 mgof Formula (I).

In a further specific aspect of the invention, the tablet comprises 80mg±4 mg of Formula (I).

In a further specific aspect of the invention, the tablet comprises 100mg±5 mg of Formula (I).

In a further specific aspect of the invention, the tablet comprises 160mg±8 mg of Formula (I).

In a further specific aspect of the invention, the tablet comprises 200mg±10 mg of Formula (I).

In a still further aspect of the invention, the tablet comprises from 1%w/w to 50% w/w of an alkaline effervescent excipient

In a still further aspect of the invention, the tablet comprises from 1%w/w to 40% w/w of an alkaline effervescent excipient

In a further aspect, the tablet comprises from 10% w/w to 30% w/w of analkaline effervescent excipients.

In a still further aspect, the tablet comprises about 20% w/w of analkaline effervescent excipients.

In a specific aspect of the invention, the tablet comprises 21.33%±5%w/w of Formula (I).

In a further aspect, the tablet comprises between 20.26% w/w to 22.40%w/w of Formula (I).

In a still further aspect, the tablet comprises between about 15% w/w toabout 25% w/w of Formula (I).

In a still farther aspect of the invention, the tablet comprises lessthan or equal to 50% w/w of an alkaline effervescent excipient.

In a further aspect, the tablet comprises less than or equal to 40% w/wof an alkaline effervescent excipient.

In a further aspect, the tablet comprises less than or equal to 30% w/wof an alkaline effervescent excipient.

In a still further aspect, the tablet comprises less than or equal to20% w/w of an alkaline effervescent excipient.

In a further aspect of the invention, the tablet comprises less than orequal to 6% w/w of a conventional lubricant.

Alternatively the use of an alternative lubricant may improve stability.

In a still further aspect of the invention, the tablet comprises lessthan or equal to 5% w/w of an alternative lubricant.

In a still further aspect of the invention, the tablet comprises lessthan or equal to 4% w/w of an alternative lubricant.

In a further aspect, the tablet comprises less than or equal to 3% w/wof an alternative lubricant.

In a still further aspect of the invention, the tablet comprises between0.25% w/w and 8% w/w of an alternative lubricant.

In a still further aspect of the invention, the tablet comprises between0.5% w/w and 5% w/w of an alternative lubricant.

In a still further aspect of the invention, the tablet comprises between1% w/w and 4% w/w of an alternative lubricant.

In a still further aspect of the invention, the tablet comprises between2.5% w/w and 3.5% w/w of an alternative lubricant.

In a further aspect, the tablet comprises about 3% w/w of an alternativelubricant.

In a further aspect of the invention, there is provided a tabletcomprising from 10% w/w to 50% w/w of Formula (I) and from 1% w/w to 50%w/w of an alkaline effervescent excipient; and optionally furthercomprising one or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a tabletcomprising from 15% w/w to 35% w/w of Formula (I) and from 10% to 40%w/w of an alkaline effervescent excipient; and further comprising one ormore pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a tabletcomprising from 15% w/w to 25% w/w of Formula (I) and from 15% w/w to25% w/w of an alkaline effervescent excipient; and further comprisingone or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a tabletcomprising about 20% w/w of Formula (I) and about 20% w/w of an alkalineeffervescent excipient; and further comprising one or morepharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a tabletcomprising from 15% w/w to 45% w/w of Formula (I) and from 10% to 40%w/w of an alkaline effervescent excipients and further comprising one ormore pharmaceutically acceptable ingredients, wherein the tabletcomprises from 10 to 200 mg of Formula (I)

In a further aspect of the invention, there is provided a tabletcomprising from 15% w/w to 40% w/w of Formula (I) and from 10% to 40%w/w of an alkaline effervescent excipients and further comprising one ormore pharmaceutically acceptable ingredients, wherein the tabletcomprises from 10 to 200 mg of Formula (I).

In a further aspect of the invention, there is provided a tabletcomprising from 15% w/w to 25% w/w of Formula (I) and from 15% to 25%w/w of an alkaline effervescent excipients and further comprising one ormore pharmaceutically acceptable ingredients, wherein the tabletcomprises 20 mg of Formula (I).

In a further aspect of the invention, there is provided a tabletcomprising from 15% w/w to 25% w/w of Formula (I) and from 15% to 25%w/w of an alkaline effervescent excipients and further comprising one ormore pharmaceutically acceptable ingredients, wherein the tabletcomprises 80 mg of Formula (I).

In a further aspect of the invention, there is provided a tabletcomprising from 15% w/w to 25% w/w of Formula (I) and from 15% to 25%w/w of an alkaline effervescent excipients and further comprising one ormore pharmaceutically acceptable ingredients, wherein the tabletcomprises 160 mg of Formula (I).

The dosage forms of this invention may include one or morepharmaceutically acceptable excipients which may be selected, forexample, from adjuvants, carriers, binders, lubricants, diluents,stabilising agents, buffering agents, emulsifying agents,viscosity-regulating agents, surfactants, preservatives, flavourings orcolorants. It will be understood that an individual excipient may bemultifunctional. Examples of pharmaceutically acceptable excipients aredescribed in the Handbook of Pharmaceutical Excipients (Fifth Edition,2005, edited by Ray C. Rowe, Paul J. Sheskey and Sian C. Owen, publishedby the American Pharmaceutical Association and the PharmaceuticalPress). As will be understood by those skilled in the art, the mostappropriate method of administering the active ingredients is dependenton a number of factors.

It will be understood that the therapeutic dose of each activeingredient administered in accordance with the present invention willvary depending upon the particular active ingredient employed, the modeby which the active ingredient is to be administered, and the conditionor disorder to be treated.

In a further aspect of the invention, optional ingredients which can beadded to make up the remainder of the tablet include one or more of thefollowing:

-   -   a) fillers which, when employed, range between for example about        10 to about 75 weight percent (e.g. about 15 to about 70 weight        percent) of the remainder of the tablet formulation;    -   b) binding agents which, when employed range between for example        about 2 to about 8 weight percent of the remainder of the tablet        formulation;    -   c) lubricants which, when employed, range from between about        0.25 and 3.5 weight percent of the remainder of the tablet        formulation; and    -   d) disintegrants which, when employed, range from between about        0.5 and 10.0 weight percent (e.g. about 5 weight percent) of the        remainder of the tablet formulation.

In a further aspect of the invention, the tablet further comprises oneor more additional ingredients independently selected from, for example:

-   -   a) fillers such as mannitol (e.g. Pearlitol 50c, Peralitol 120c        or Pearlitol 160c) or microcrystalline celluloses (e.g. MCC        Avicel PH 101, Emcocel 90M, etc.);    -   b) binding agents such as Plasdone K29/32, Povidone,        microcrystalline celluloses or Kollidon K30;    -   c) lubricants such as glyceryl dibehenate;    -   d) disintegrants such as sodium starch glycolate, for example        ExploTab or Glycolys LV;

In a further aspect of the invention, the tablet optionally furthercomprises a suitable coating, for example a film coating. A coating canbe used to provide protection against, for example, moisture ingress ordegradation by light, to colour the formulation, or to modify or controlthe release of Formula (I) from the formulation.

In a yet further aspect of the invention, the pharmaceutical compositioncomprises the following components by weight:

Composition A (mg) Composition B (mg) Formula (I) 20.00 Formula (I)80.00 Microcrystalline cellulose 14.06 Microcrystalline cellulose 56.25Mannitol 29.22 Mannitol 116.87 Magnesium carbonate 18.75 Magnesiumcarbonate 75.00 Hydroxypropyl cellulose 1.88 Hydroxypropyl cellulose7.50 Sodium starch glycollate 7.03 Sodium starch glycollate 28.13Glyceryl dibehenate 2.81 Glyceryl dibehenate 11.25

In a yet further aspect of the invention, the pharmaceutical compositioncomprises the following components (% w/w):

Compositions A and B (% w/w) Formula (I) 21.33 Microcrystallinecellulose 15.00 Mannitol 31.17 Magnesium carbonate 20.00 Hydroxypropylcellulose 2.00 Sodium starch glycollate 7.50 Glyceryl dibehenate 3.00

In a still further aspect, the invention comprises a tablet formed fromthe pressing of composition A and/or composition B into tablet form.

In a further aspect of the invention, there is provided a process forthe preparation of a pharmaceutical composition which process comprisesthe following steps:

-   -   Step A—comprises mixing Formula (I) with an alkaline        effervescent excipient optionally in the presence of one or more        pharmaceutically acceptable ingredients. In a further aspect,        Step A is carried out in the presence of one or more additional        fillers (such as mannitol) and optionally in the presence of one        or more pharmaceutically acceptable ingredients. In a still        further aspect, Step A is carried out in the presence of one or        more additional fillers (such as mannitol) and optionally in the        presence of one or more binding agents and/or one or more        disintegrants.    -   Step B—comprises adding purified water and/or binder solution        into the powder mixture from Step A above and mixing to form        granules and optionally passing through a filter screen to        break-up agglomerates. In a further aspect between about 10% and        45% by weight of purified water is added into the powder        mixture.    -   Step C—comprises drying the granules produced in Step B above        until an LOD of less than 10% (e.g. less than 5%) is achieved,        to provide dried granules.    -   Step D—comprises optionally milling the dried granules from Step        C.    -   Step E—optionally, comprises mixing the milled granules from        Step D with an alkaline effervescent excipient.

In a farther aspect of the invention there is provided a process for thepreparation of a pharmaceutical composition which process (wetgranulation process) comprises:

-   -   a) blending Formula (I) with an effervescent agent, one or more        additional fillers (such as mannitol) and optionally in the        presence of one or more binding agents and/or one or more        disintegrants and/or one or more other excipients;    -   b) adding between about 10% and 45% by weight of purified water        and/or binder solution into the powder mixture of a) above and        mixing to form enlarged granules and optionally passing through        a filter screen to break-up large agglomerates; and    -   c) drying the enlarged granules produced in b) above until an        LOD of less than 10% (e.g. less than 5%) is achieved, to provide        dried granules.

Alternatively, in another aspect of the invention, there is provided aprocess for the preparation of a pharmaceutical composition whichprocess comprises the following steps

-   -   Step A—mixing Formula (I) optionally with an alkaline        effervescent excipient optionally in the presence of one or more        pharmaceutically acceptable ingredients. In a further aspect,        Step A is carried out in the presence of one or more additional        fillers (such as mannitol) and optionally in the presence of one        or more pharmaceutically acceptable ingredients. In a still        further aspect, Step A is carried out in the presence of one or        more additional fillers (such as mannitol) and optionally in the        presence of one or more binding agents and/or one or more        disintegrants.    -   Step B—comprises adding purified water and/or binder solution        into the powder mixture from Step A above and mixing to form        granules and optionally passing through a filter screen to        break-up agglomerates. Typically, between about 10% and 45% by        weight of purified water and/or binder solution is added into        the powder mixture.    -   Step C—comprises drying the granules produced in Step B above        until an LOD of less than 10% (e.g. less than 5%) is achieved,        to provide dried granules.    -   Step D—comprises milling the dried granules from Step C to give        milled granules    -   Step E—comprises mixing the milled granules from Step D with an        effective amount of an alkaline effervescent excipient.

In a further aspect of the invention there is provided a process for thepreparation of a pharmaceutical composition which process (wetgranulation process) comprises:

-   -   a) blending Formula (I) with one or more additional fillers        (such as mannitol) and optionally in the presence of one or more        binding agents and/or one or more disintegrants and/or one or        more other excipients;    -   b) adding between about 10% and 45% by weight of purified water        and/or binder solution into the powder mixture of a) above and        mixing to form granules and optionally passing through a filter        screen to break-up agglomerates;    -   c) drying the granules produced in b) above until an LOD of less        than 10% (e.g. less than 5%) is achieved, to provide dried        granules;    -   d) milling the dried granules produce in c) to give milled        granule; and    -   e) mixing the milled granules from d) with an alkaline        effervescent excipient.

In another of its method aspects, this invention further comprisesmilling the dried granules. In one aspect, the dried granules are milledso that about 90 weight percent have a particle size between about 25 μmto about 3500 μm in diameter.

In yet another aspect, the dried, milled, granules are mixed with aconventional and/or alternative lubricant, and then the resultingpharmaceutical composition is tabletted. Conventional and alternativelubricants include glyceryl dibehenate, sodium stearyl fumarate,magnesium stearate, colloidal silica and talc.

In a further aspect of the invention, the alternative lubricant (such asglyceryl dibehenate) can be added to the dry granules prior to milling,and then the resulting pharmaceutical composition is milled and thentabletted.

In another aspect, this invention provides a wet granulated formulationcomprising between 10% w/w to 60% w/w of Formula (I) and an amount of analkaline effervescent excipient that is sufficient to providesatisfactory in vitro dissolution; and further comprising one or morepharmaceutically acceptable ingredients.

In another aspect of the invention the wet granulated formulationcomprises between 15% w/w to 50% w/w of Formula (I).

In a further aspect, the wet granulated formulation comprises between15% w/w to 40% w/w of Formula (I).

In a further aspect, the wet granulated formulation comprises between15% w/w to 25% w/w of Formula (I).

In another aspect of the invention the wet granulated formulationcomprises about 20% w/w of Formula (I).

In a specific aspect of the invention, the wet granulated formulationcontains 21.33%±5% w/w of Formula (I).

In a further aspect, the wet granulated formulation comprises between20.26% w/w to 22.40% w/w of Formula (I).

In a still further aspect of the invention, the wet granulatedformulation comprises from 1% w/w to 50% w/w of an alkaline effervescentexcipient.

In a further aspect, the wet granulated formulation comprises from 1%w/w to 40% w/w of an alkaline effervescent excipient.

In a further aspect, the wet granulated formulation comprises from 10%w/w to 30% w/w of an alkaline effervescent excipient

In a still further aspect, the wet granulated formulation comprises from15% w/w to 25% w/w of an alkaline effervescent excipient

In a still further aspect, the wet granulated formulation comprisesabout 20% w/w of an alkaline effervescent excipient

In a further aspect of the invention, there is provided a wetgranulation formulation comprising from 10% w/w to 50% w/w of Formula(I) and from 1% w/w to 50% w/w of an effervescent agent; and furthercomprising one or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a wetgranulation formulation comprising greater from 10% w/w to 45% w/w ofFormula (I) and from 10% w/w to 45% w/w of an alkaline effervescentexcipient; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a wetgranulation formulation comprising from 15% w/w to 25% w/w of Formula(I) and from 15% to 25% w/w of an alkaline effervescent excipient; andfurther comprising one or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a wetgranulation formulation comprising about 20% w/w of Formula (I) andabout 20% w/w of an alkaline effervescent excipient; and furthercomprising one or more pharmaceutically acceptable ingredients.

In another aspect of the invention the wet granulation formulationcomprises Formula (I), water, an alkaline effervescent excipient,additional filler(s), binding agent(s) and disintegrant(s).

In another aspect, this invention provides a tablet formed bycompressing the wet granulated formulation.

In a further aspect of the invention, there is provided a furtherprocess for the preparation of a pharmaceutical composition as definedabove which process comprises passing the mixture of Step A abovethrough a compactor to produce dry granules (Step D).

In a further aspect of the present invention there is provided a processfor the manufacture of a pharmaceutical composition which process(roller compaction process) comprises:

-   -   (a) blending Formula (I) with an alkaline effervescent        excipient, one or more additional fillers (such as mannitol) and        optionally in the presence of one or more binding agents and/or        one or more disintegrants and/or one or more other excipients;    -   (b) passing the mixture of (a) above through a compactor to        produce dry granules.

In another of its method aspects, this invention further comprisesmilling the dried granules. In one aspect, the dried granules are milledso that about 90 weight percent have a particle size between about 25 μmto about 3500 μm in diameter.

In yet another aspect, the dried, milled, granules are mixed with alubricant, and then the resulting pharmaceutical composition istabletted. Suitable lubricants include glyceryl dibehenate, sodiumstearyl fumarate, magnesium stearate, colloidal silica and talc.

In yet another aspect of the present invention there is provided aprocess for the manufacture of a pharmaceutical composition whichprocess (roller compaction process) comprises:

-   -   (a) blending Formula (I) with an alkaline effervescent        excipient, one or more additional fillers (such as mannitol) and        optionally in the presence of one or more binding agents and/or        one or more disintegrants and/or one or more other excipients;    -   (b) passing the mixture of (a) above through a compactor to        produce dry granules.

In another of its method aspects, this invention further comprisesmilling the dried granules. In one aspect, the dried granules are milledso that about 90 weight percent have a particle size between about 25 μmto about 3500 μm in diameter.

In yet another aspect of the present invention there is provided aprocess for the manufacture of a pharmaceutical composition whichprocess (roller compaction process) comprises:

-   -   (a) blending Formula (I) optionally with an alkaline        effervescent excipient, one or more additional fillers (such as        mannitol) and optionally in the presence of one or more binding        agents and/or one or more disintegrants and/or one or more other        excipients;    -   (b) passing the mixture of (a) above through a compactor to        produce dry granules.

The dried, milled, granules are then mixed with an alkaline effervescentexcipient.

In yet another aspect, the dried, milled, granules are mixed with alubricant, and then the resulting pharmaceutical composition istabletted. Suitable lubricants include glyceryl dibehenate, sodiumstearyl fumarate, magnesium stearate, colloidal silica and talc.

In an alternative aspect of the invention, the lubricant (such asglyceryl dibehenate) can be added to the dry granules prior to milling,and then the resulting pharmaceutical composition is milled and thentabletted.

In another aspect, this invention provides a roller compactionformulation comprising greater than 10% w/w of Formula (I) and an amountof an alkaline effervescent excipient that is sufficient to providesatisfactory in vitro dissolution; and further comprising one or morepharmaceutically acceptable ingredients.

In another aspect of the invention the roller compaction formulationcomprises between 10% w/w to 60% w/w of Formula (I).

In a further aspect, the roller compaction formulation comprises between15% w/w to 50% w/w of Formula (I).

In a still further aspect, the roller compaction formulation comprisesbetween 15% w/w to 45% w/w of Formula (I).

In a still further aspect, the roller compaction formulation comprisesbetween 15% w/w to 40% w/w of Formula (I).

In a still further aspect, the roller compaction formulation comprisesbetween 15% w/w to 25% w/w of Formula (I).

In another aspect of the invention the roller compaction formulationcomprises about 20% w/w of Formula (I).

In a specific aspect of the invention, the roller compaction formulationcontains 21.33%±5% w/w of Formula (I).

In a further aspect, the roller compaction formulation contains 20.26%w/w to 22.40% w/w of Formula (I).

In a still further aspect of the invention, the roller compactionformulation comprises from 1% w/w to 50% w/w of an alkaline effervescentexcipient.

In a further aspect, the roller compaction formulation comprises from 1%w/w to 40% w/w of an alkaline effervescent excipient.

In a still further aspect, the roller compaction formulation comprisesfrom 10% w/w to 30% w/w of an alkaline effervescent excipient.

In a still further aspect, the roller compaction formulation comprisesfrom 15% w/w to 25% w/w of an alkaline effervescent excipient.

In a still further aspect, the roller compaction formulation comprisesabout 20% w/w of an alkaline effervescent excipient.

In a further aspect of the invention, there is provided a rollercompaction formulation comprising from 15% w/w to 45% of Formula (I) andfrom 10% w/w to 40% w/w of an alkaline effervescent excipient; andfurther comprising one or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a rollercompaction formulation comprising from 15% w/w to 25% w/w of Formula (I)and from 15% w/w to 25% w/w of an alkaline effervescent excipient; andfurther comprising one or more pharmaceutically acceptable ingredients.

In another aspect of the invention the roller compaction formulationcomprises Formula (I), an alkaline effervescent excipient, additionalfiller(s), binding agent(s) and disintegrant(s).

In another aspect, this invention provides a tablet formed bycompressing the roller compaction formulation.

In a further aspect of the invention there is provided a process for themanufacture of a pharmaceutical composition which process (directcompression process) comprises:

-   -   (a) blending Formula (I) with an alkaline effervescent        excipient, one or more additional fillers (such as mannitol) and        optionally in the presence of one or more binding agents and/or        one or more disintegrants and/or one or more lubricants and/or        one or more other excipients;    -   (b) compressing the mixture of (a) above.

In another aspect of the invention the direct compression formulationcomprises Formula (I), an alkaline effervescent excipient, additionalfiller(s), binding agent(s), lubricant(s) and disintegrant(s).

In another aspect, this invention provides a tablet formed directly bycompressing the mixture of (a) above.

In another aspect, this invention provides a direct compressionformulation comprising greater than 10% w/w of Formula (I) and an amountof an alkaline effervescent excipient that is sufficient to providesatisfactory in vitro dissolution; and further comprising one or morepharmaceutically acceptable ingredients.

In another aspect of the invention the direct compression formulationcomprises between 10% w/w to 60% w/w of Formula (I).

In a further aspect, the direct compression formulation comprisesbetween 10% w/w to 50% w/w of Formula (I).

In a still further aspect, the direct compression formulation comprisesbetween 15% w/w to 40% w/w of Formula (I).

In a still further aspect, the direct compression formulation comprisesbetween 15% w/w to 25% w/w of Formula (I).

In another aspect of the invention the direct compression formulationcomprises about 20% w/w of Formula (I).

In a specific aspect of the invention, the direct compressionformulation contains 21.33%±5% w/w of Formula (I).

In a further aspect, the direct compression formulation contains 20.26%w/w to 22.40% w/w of Formula (I).

In a still further aspect of the invention, the direct compressionformulation comprises from 1% w/w to 50% w/w of an alkaline effervescentexcipient.

In a further aspect, the direct compression formulation comprises from1% w/w to 40% w/w of an alkaline effervescent excipient

In a still further aspect, the direct compression formulation comprisesfrom 10% to 30% w/w of an alkaline effervescent excipient.

In a still further aspect, the direct compression formulation comprisesfrom 15% to 25% w/w of an alkaline effervescent excipient.

In a still further aspect, the direct compression formulation comprisesabout 20% w/w of an alkaline effervescent excipient.

In a further aspect of the invention, there is provided a directcompression formulation comprising from 10% w/w to 50% w/w of Formula(I) and from 1% w/w to 50% w/w of an effervescent agent; and furthercomprising one or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a directcompression formulation comprising from 15% w/w to 45% w/w of Formula(I) and from 10% w/w to 40% w/w of an effervescent agent; and furthercomprising one or more pharmaceutically acceptable ingredients.

In a further aspect of the invention, there is provided a directcompression formulation comprising from 15% w/w to 25% w/w of Formula(I) and from 15% w/w to 25% w/w of an effervescent agent; and furthercomprising one or more pharmaceutically acceptable ingredients.

The pharmaceutical composition and/or tablet and/or wet granulationformulation and/or roller compaction formulation and/or directcompression formulation can additionally and optionally include acolourant, as long as it is approved and certified by the FDA. Forexample, exemplary colours include allura red, acid fuschin D,napthalone red B, food orange 8, eosin Y, phyloxine B, erythrosine,natural red 4, carmine, red iron oxide, yellow iron oxide, black ironoxide, titanium dioxide and the like.

Sweetening agents can also be added to the pharmaceutical compositionand/or tablet and/or wet granulation formulation and/or rollercompaction formulation and/or direct compression formulation or to thethe outer core of the tablet to create or add to the sweetness.Saccharide fillers and binders, e.g. mannitol, lactose, and the like,can add to this effect. For example, cyclamates, saccharin, aspartame,acesulfame K (Mukherjee (1997) Food Chem. Toxicol. 35:1177-1179), or thelike (Rolls (1991) Am. J. Clin. Nutr. 53:872-878), can be used.Sweeteners other than sugars have the advantage of reducing the bulkvolume of the pharmaceutical composition and/or tablet (core tabletand/or coat) and/or wet granulation formulation and/or roller compactionformulation and/or direct compression formulation and not effecting thephysical properties of the tablet.

The pharmaceutical composition and/or tablet and/or wet granulationformulation and/or roller compaction formulation and/or directcompression formulation can additionally and optionally be coated usinga conventional pan coater. The film coat may be applied by spraying anaqueous suspension of the coating ingredients onto the tablet cores.

Definitions

As used herein, the term “effervescent excipient” refers to anypharmaceutically acceptable material which evolves a gas in response toa stimulus, for example the evolution of carbon dioxide onacidification. An example of an effervescent excipient is a carbonate,for example a metal carbonate (such as sodium carbonate, potassiumcarbonate, magnesium carbonate, calcium carbonate or aluminiumcarbonate) or an organic carbonate (such as disodium glycine carbonate,dimethyl carbonate or ethylene carbonate). A further example of aneffervescent excipient is a bicarbonate, for example a metal bicarbonate(such as sodium hydrogen carbonate or potassium hydrogen carbonate).

As used herein, the term “alkaline” refers to a material which inducesan increase in pH when added to an aqueous system. The term “alkalineexcipient” refers to any pharmaceutically acceptable material which isalkaline, for example an inorganic base such as disodium hydrogenphosphate or sodium hydroxide.

An alkaline effervescent excipient is a pharmaceutically acceptablematerial having both effervescent activity and alkaline properties, forexample sodium hydrogen carbonate, potassium hydrogen carbonate,magnesium carbonate and sodium carbonate. For the avoidance of doubt,each of the alkaline effervescent excipients referred to aboverepresents a separate and independent aspect of the invention. In oneparticular aspect of the invention, the alkaline effervescent excipientis selected from a metal carbonate or a metal bicarbonate. In anotherparticular aspect of the invention, the alkaline effervescent excipientis selected from magnesium carbonate, sodium hydrogen carbonate,potassium hydrogen carbonate, or sodium carbonate. In a furtherparticular aspect of the invention, the alkaline effervescent excipientis magnesium carbonate.

As used herein, the term “binding agent” refers to a pharmaceuticallyacceptable compound or composition added to a formulation to hold theactive pharmaceutical ingredient and inactive ingredients together in acohesive mix. Dry binders used for direct compaction must exhibitcohesive and adhesive forces so that when compacted the particlesagglomerate. Binders used for wet granulation are hydrophilic andsoluble in water and are usually dissolved in water to form a wet massthat is then granulated. Examples of suitable binding agents includes,but are not limited to, Povidone, Plasdone K29/32, Plasdone S-630,hydropropyl cellulose, methylcellulose, polyvinylpyrrolidone, aluminiumstearate, hydroxypropylmethylcellulose and the like. It is possible forsuch binding agents to additionally act as water sequestering agents(e.g. Povidone).

As used herein, the term “filler” refers to any pharmaceuticallyacceptable material or composition added to a formulation to add bulk.Suitable fillers include, but are not limited to, mannitol, lactose,microcrystalline cellulose, silified microcrystalline cellulose anddicalcium phosphate.

As used herein, the term “lubricant” refers to any pharmaceuticallyacceptable agent which reduces surface friction, lubricates the surfaceof the granule, decreases tendency to build-up of static electricity,and/or reduces friability of the granules. Thus, lubricants can serve asanti-agglomeration agents. Conventional lubricants include stearic acidand related compounds such as magnesium stearate and sodium stearylfumarate. Alternative lubricants include glyceryl dibehenate, colloidalsilica, talc, other hydrogenated vegetable oil or triglycerides.Examples of suitable alternative lubricants include, but are not limitedto, glyceryl dibehenate.

As used herein, the term “disintegrant” refers to materials added to thecomposition to help it break apart (disintegrate) and release themedicaments. Examples of disintegrants include, but are not limited to,non-saccharide water soluble polymers, such as cross-linked povidine.Other disintegrants that can also be used include, e.g. croscarmellosesodium, sodium starch glycolate, and the like, e.g. see Khattab (1992)J. Pharm. Pharmacol. 45:687-691.

The term “drying” and “dried” refer to a process which decreases thewater content of a composition to a desired level.

The terms “compressing”, “molding” and “pressing” refer to the processof applying compressive force to a formulation (powder or granules), aswithin a die, to form a tablet. The terms “compressed tablet” and“pressed tablet” mean any tablet formed by such a process.

The term “filming” refers to the adhesion of material to tablet punchsurfaces. If sufficient material is allowed to build on punch surfacesthen, among other defects, tablet weights may reduce below acceptablelimits. (Journal of Pharmaceutical Sciences, Vol. 93(2), 2004).

The term “tablet” is used in its common context, and refers to a solidcomposition made by compressing and/or molding a mixture of compositionsin a form convenient for swallowing or application to any body cavity.

As used herein, “tablet strength” is calculated based upon the amount ofCompound I.

As used herein, “percent loading” is calculated by reference to thepercentage by weight of Compound I

The term “low pH” refers to a measured pH of less than 5, such as lessthan 3, for example between 0 and 3.

The term “satisfactory in vitro dissolution” refers to a percentdissolution of greater than or equal to 70% within 30 minutes in asuitable dissolution medium at 37° C.±0.5° C. as measured using thegeneral procedure of the United States Pharmacopeia (Apparatus 2).

The term “stable formulation” refers to a formulation which, followingstorage for 4 weeks at elevated temperature and humidity, such as 40° C.and 75% relative humidity, exhibits water absorption of less than 10%,such as less than 5%, for example between 0 and 5%; and/or chemicaldegradation of less than 3%, such as less than 2.5%, for example between0 and 2.5%; and/or which exhibits satisfactory in vitro dissolution.

The term “manufacturability” means the extent to which a product can bemanufactured with relative ease at minimum cost and maximum reliability.

DESCRIPTION OF FIGURES

FIG. 1 shows a plot of the percentage dissolution using pH1.3hydrochloric acid/sodium chloride buffer of ten alternative tabletformulations.

FIG. 2 shows a plot of the percentage dissolution using pH1.3hydrochloric acid/sodium chloride buffer of a further nineteenalternative tablet formulations.

FIG. 3 shows a plot of the percentage dissolution using pH6.8 phosphatebuffer of five alternative tablet formulations in which the lubricantcontent was varied.

FIG. 4 shows a plot of the percentage dissolution using pH1.3hydrochloric acid/sodium chloride buffer for ten alternative tabletformulations in which Formula (I), magnesium carbonate and lubricant wasvaried.

FIG. 5 shows a plot of the percentage dissolution using pH6.8 phosphatebuffer for ten alternative tablet formulations in which Formula (I),magnesium carbonate and lubricant was varied.

EXAMPLES

The invention is further understood by reference to the followingexamples, which are intended to be purely exemplary of the invention.The present invention is not limited in scope by the exemplifiedaspects, which are intended as illustrations of single aspects of theinvention only. Various modifications of the invention in addition tothose described herein will become apparent to those skilled in the artfrom the foregoing description and accompanying figures. Suchmodifications fell within the scope of the appended claims.

In the examples below as well as throughout the application, thefollowing abbreviations have the following meanings. If not defined, theterms have their generally accepted meanings.

-   -   API=ActiveI Pharmaceutical Ingredient    -   CCS=croscarmellose sodium    -   CrosPov=crospovidone    -   BP=British Pharmacopoeia 2012    -   DCPA=dicalcium Phosphate (anhydrous)    -   DCPD=dicalcium Phosphate (dihydrate)    -   Glydb=glyceryl dibehenate    -   HPC=hydroxypropylcellulose    -   L-HPC=hydroxypropylcellulose, low-substituted    -   LOD=loss on drying    -   Mag carb=magnesium carbonate    -   MCC=cellulose, microcrystaline    -   MgSt=magnesium stearate    -   min=minute    -   ml=milliliter    -   nm=nanometer    -   JP=Japanese Pharmacopeia 15^(th) Edition, English Version        (Society of Japanese Pharmacopoeia) 2006    -   PhEur=European Pharmacopoeia 6^(th) Edition (Directorate for the        Quality of Medicines of the Council of Europe) 2009    -   rpm=revolutions per minute    -   SLS=sodium lauryl sulphate    -   SSF=sodium stearyl fumurate    -   SSG=sodium starch glycolate    -   USP/USP-NF=United States Pharmacopeia 31/National Formulary 26        (The United States Pharmacopeia Convention) 2008    -   UV=ultraviolet    -   w/w=weight for weight

Table 1 below shows materials used, pharmacopeial status, grade andsupplier.

TABLE 1 Material Pharmacopeia Grade Supplier Mannitol PhEur Pearlitol160c Roquette Freres USP-NF S.A. (France) JP Cellulose, PhEur Avicel ®FMC Biopolymer microcrystalline USP-NF PH-101 (Ireland) JP SalicifiedUSP-NF Prosolv ® 90 Rettenmaier UK Ltd cellulose, (UK) microcrystallineDicalcium PhEur Calipharm A Innophos (USA) phosphate BP (anhydrous) JPUSP Dicalcium PhEur Calipharm D Innophos (USA) phosphate BP (dihydrate)JP USP Sodium PhEur N/A Dr Paul Lohmann bicarbonate BP (Germany) JP USPCalcium PhEur N/A Dr Paul Lohmann carbonate BP (Germany) (heavy) JP USPMagnesium PhEur N/A Dr Paul Lohmann carbonate BP (Germany) (heavy) JPUSP Disodium PhEur N/A Budenheim (USA) phosphate BP (dibasic) JP USP-NFSodium starch Ph Eur Glycolys LV Roquette Freres glycolate USP-NF S.A.(France) Hydroxypropyl- JP L-HPC Shin Etsu, (Japan) cellulose, low-USP-NF substituted Croscarmellose Ph Eur Ac-di-Sol FMC Biopolymer sodiumUSP (Ireland) JP Crospovidone PhEur Polyplasdone Ashland Speciality BPXL Ingredients, (UK) USP-NF Hydroxypropyl- PhEur Klucel EXF AshlandSpeciality cellulose BP Ingredients (UK) USP-NF JP Hydroxypropyl- PhEurPharmacoat Shin Etsu, (Japan) methylcellulose BP 603 (hypromellose)USP-NF JP Sodium lauryl USP N/A Sigma Aldrich sulphate NF (UK) (Sodiumdodecyl sulfate) Magnesium PhEur NF Non Mallinckrodt stearate USP-NFBovine (USA) JP Sodium stearyl PhEur Pruv JRS Pharma, fumurate BP(Germany) USP-NF Glyceryl PhEur Compritol 888 Gattefosse dibehenate USPATO (France) Opadry II Biege N/A N/A Colorcon (USA)

Table 2 below shows equipment used, model and supplier.

TABLE 2 Make Model Supplier Pro-C-ept Mi-pro Pro-C-ept, Belgium DiosnaP1/6 Dierks & Söhne Gmbh, Osnabrück, Germany Collette Gral 10 & ColletteMachines, Belgium Gral 25 Quadro Comil U3 & Quadro Engineering, Comil194 Waterloo, Canada WAB Turbula T2F Willy A. Bachofen AG, Muttenz,Switzerland Copley Mobile Mobile Blender Copley Scientific, Nottingham,UK Blender Aeromatic Strea 1 Casburt Pharmaceutical Equipment,Stoke-on-Trent, UK Aeromatic- MP1 Aeromatic Fielder, Eastleigh, UKFielder Vector MFL.01 Vector Corporation, Marion, IA, U.S.A Glatt 59PGlatt GmbH, Binzen, Germany Riva Piccola-Nova, RivaSA, Buenos Aires,Argentina Manesty F3 Manesty, Knowsley, UK Korsch Korsch XL100 KorschAG, Berlin, Germany Riva Riva mini-press RivaSA, Buenos Aires, ArgentinaRiva Piccola W.I.P RivaSA, Buenos Aires, Argentina O'Hara Labcoat II-XO'hara technologies inc, Ontario, Canada

Example 1: Assessment of Dissolution Performance of Ten AlternativeTablet Forms

It has been found that the rheology of Formula (I) can change undercertain conditions. In particular, Formula (I) can convert from acrystalline powder to a highly viscous material under low pH and at highconcentration (both conditions need to be met simultaneously).Theoretically, these conditions will be met in the microenvironment ofthe tablet matrix either using a low pH dissolution method (e.g. pH1.3)or in the stomach. The relative surface area of Formula (I) reduces whenthe viscous material forms and this is associated with a reduced rate ofsolubilisation of Formula (I). This can be observed as a reduced rate ofdissolution using a low pH method.

Based on this fundamental understanding, there are two hypotheticalmechanisms to avoid the rheologial transformation; first, to not allowFormula (I) to solubilise in a low pH environment (Hypothesis I);second, if dispersion in a low pH environment cannot be avoided, todisperse Formula (I) rapidly before the transformation can occur(Hypothesis II). Hypothesis II is dependent on the concentration ofFormula (I) in the tablet matrix as higher concentrations of Formula (I)reduce the likelihood of rapid dispersion. Ten different prototypetablets were prepared from a wet granulation formulation using methodswell known to those skilled in the art. The composition of each of thesetablets is set out in Table 3.

TABLE 3 Formula Mannitol pH Buffer Disintegrant (I), MCC type level typeType HPC Run % w/w (level, % w/w) (% w/w) (% w/w) (% w/w) (% w/w) 1 20Avicel PH101 20 N/A SSG (7.5) 3 (48.5) 2 40 Avicel PH101 14.2 N/A SSG(7.5) 3 (34.3) 3 40 Avicel PH101 11.8 NaHCO₃ SSG (7.5) 3 (16.7) (20.0) 440 Avicel PH101 11.8 CaCO₃ (20.0) SSG (7.5) 3 (16.7) 5 40 Avicel PH10111.8 Na₂HPO₄ SSG (7.5) 3 (16.7) (20.0) 6 40 Avicel PH101 11.8 MgCO₃(20.0) SSG (7.5) 3 (16.7) 7 40 Prosolv ® SMCC 14.2 N/A SSG (7.5) 3(34.3) 8 40 N/A 31.0 NaHCO₃ SSG (5) 3 (20.0) 9 20 Avicel PH101 20 N/ACCS (7.5) 3 (48.5) 10 20 Avicel PH101 20 N/A CrosPov 3 (48.5) (7.5)

Run 1 is comparable to the Phase 1 clinical formulation and is thepositive control. Run 2 is a negative control as it contains a highconcentration of Formula (1) and has no alkalising agent. Run 5 testsHypothesis I (Na₂HPO₄ is an alkalising agent). Runs 7, 9 and 10 testHypothesis II (no alkalising agent, but varying disintegrants). Runs3,4, 6 and 8 test both Hypotheses I and II (they containcarbonate/bicarbonate alkalizing agents which both increase the pHmicroenvironment and liberate carbon dioxide in acidic conditions;carbon dioxide liberation can help to disperse Formula (I)).

Formula (I) and the excipients (except lubricant) described in Table 1(total batch size approximately 250 g) were charged to amixer-granulator (Diosna, 1 liter bowl, P1/6) and mixed. Purified waterwas added to the powders with further mixing until a suitable wet masswas formed. The resultant granules were dried to appropriate moisturecontent (≤2% w/w LOD) using a fluid bed dryer (Vector, MFL.01) with aninlet air temperature of 65° C. The dried granules were milled using anappropriately sized screen (1 mm, Quadro Comil U3).

SSF was then added to the granules (Table 4), which were then blended(WAB turbula) for 10 mins at 55 rpm before compressing into tablet coresusing conventional tabletting equipment (Manesty F3 tablet press) Table4

Milled granules from composition variant SSF Addition (Table 1) (% w/w)1 1 2 1 3 2 4 2 5 2 6 2 7 2 8 2 9 2 10 2

Concentration of SSF in the compositions was increased after Run 2 toallow viable processability during compression. Theoretically, thiswould reduce adhesion of material to tablet punches and dies(Pharmaceutical Powder Compaction Technology, edited by Goran Alderbornand Christer Nystrdm, Informa Healthcare, New York, 2008). However,increasing level of lubricant also typically reduces rate of dissolutiondue to the hydrophobic nature of the lubricant.

Further process conditions are given in Table 5.

TABLE 5 Total Total Water granulation time Run Chopper (rpm) Impellor(rpm) Added (ml) (min) 1 1000 300 81 4.1 2 1000 300 40 2.0 3 1500 750 656.5 4 1500 750 80 8.0 5 1500 750 80 8.0 6 1500 750 65 6.5 7 1500 750 707.0 8 1500 750 25 2.5 9 1500 750 80 8.0 10 1500 750 70 7.0

Impellor and chopper speeds were increased after Run 2 to allow viableprocessability during compression. Theoretically, increasing theseprocess conditions increases granule density (Powder Technology, 117, pp3-39, 2001) which aids granule flow and reduces punch filming. However,increasing granule density also typically reduces rate of dissolution.

Similarly, increasing total water added (Powder Technology, 88, pp15-20, 1996) and granulation time (granule densification is a rateprocess) are also likely to increase granule density and thus reducedissolution rate.

Dissolution was determined according to the general procedure of theUnited States Pharmacopeia using Apparatus 2 with pH1.3 hydrochloricacid and sodium chloride buffered solution at 37° C.±0.5° C. and stirrerspeed of 50 rpm. At 15, 30 and 60 minutes dissolution media waswithdrawn and the concentration of Formula (I) in solution wasdetermined by UV spectroscopy at a wavelength of 311 nm against anexternal standard solution. Dissolution profiles are shown in FIG. 1,the dissolution data is presented in Table 6.

TABLE 6 Run 15 minutes 30 minutes 60 minutes 1 67.4 76.1 85.8 2 42.950.7 62.6 3 100.6 99.9 100.3 4 65.3 77.0 86.1 5 29.4 43.8 53.1 6 92.495.1 96.7 7 48.1 55.5 65.7 8 100.1 99.3 99.7 9 53.2 63.4 78.0 10 54.963.4 74.4

Example 2: Assessment of Tablet Punch Filming of Ten Alternative TabletForms

Ten different prototype tablets were prepared from a wet granulationformulation using methods well known to those skilled in the art. Thecomposition and manufacturing process of each of these tablets isdescribed in Example 1.

Material adhesion to tablet punch surfaces (described below as‘filming’) is a well known tabletting process defect (Journal ofPharmaceutical Sciences, Vol. 93(2), 2004). Extent of filming wasvisually assessed for each formulation and reported in Table 7.

TABLE 7 Run Filming 1 ★★ 2 ★★★ 3 ★ 4 No filming 5 No filming 6 ★ 7 ★★ 8★★★ 9 No filming 10 No filming ★ = minor ★★ = moderate ★★★ = severe

Example 3: Assessment of Tablet Water Absorption of Ten AlternativeTablet Forms

Ten different prototype tablets were prepared from a wet granulationformulation using methods well known to those skilled in the art. Thecomposition and manufacturing process of each of these tabletcompositions is described in Example 1.

Extent of water absorption was measured for each formulation (see Table8). The tablets were exposed to a controlled environment (40° C. and 75%relative humidity) for one month.

TABLE 8 Water Absorption Run (% w/w) 1 8.5 2 7.9 3 32.2 4 13.5 5 27.9 64.4 7 7.6 8 32.2 9 9.1 10 8.8

Example 4: Assessment of Dissolution Performance of a Further NineteenAlternative Tablet Forms

Run 6 (Examples 1, 2 and 3) was selected for further developmentbecause, unlike other compositions, it showed a marked improvement inpH1.3 dissolution (FIG. 1), an improvement in punch filming (Table 7)and low water absorption (Table 8).

A further nineteen different prototype tablets were prepared from a wetgranulation formulation using methods well known to those skilled in theart. The composition of each of these tablets is qualitatively similarto Run 6. Quantitative compositions are set out in Table 9.

TABLE 9 Formula Mag Water (I) MCC Mannitol Carb HPC SSG SSF Addition Run(% w/w) (% w/w) (% w/w) (% w/w) (% w/w) (% w/w) (% w/w) (% w/w) 1 21.30.0 59.7 10.0 1.0 5.0 3.0 20.10 2 21.3 30.0 29.7 10.0 1.0 5.0 3.0 26.203 21.3 0.0 39.7 30.0 1.0 5.0 3.0 15.00 4 21.3 34.8 0.0 34.8 1.0 5.0 3.045.00 5 21.3 0.0 57.7 10.0 3.0 5.0 3.0 20.00 6 21.3 30.0 27.7 10.0 3.05.0 3.0 35.00 7 21.3 0.0 37.7 30.0 3.0 5.0 3.0 15.00 8 21.3 33.8 0.033.8 3.0 5.0 3.0 40.20 9 21.3 0.0 54.7 10.0 1.0 10.0 3.0 20.00 10 21.330.0 24.7 10.0 1.0 10.0 3.0 30.00 11 21.3 0.0 34.7 30.0 1.0 10.0 3.030.40 12 21.3 32.3 0.0 32.3 1.0 10.0 3.0 40.00 13 21.3 0.0 52.7 10.0 3.010.0 3.0 20.30 14 21.3 30.0 22.7 10.0 3.0 10.0 3.0 32.50 15 21.3 0.032.7 30.0 3.0 10.0 3.0 32.40 16 21.3 31.3 0.0 31.3 3.0 10.0 3.0 35.30 1721.3 15.0 31.2 20.0 2.0 7.5 3.0 40.00 18 21.3 15.0 31.2 20.0 2.0 7.5 3.040.00 19 21.3 15.0 31.2 20.0 2.0 7.5 3.0 40.30

Formula (I) and the excipients described in Table 9 (total batch sizeapproximately 1.5 kg) were charged to a mixer-granulator (Colette Gral10) and mixed. Purified water (Ranging from 15% w/w to 45% w/w as setout in Table 9) was added to the powders with further mixing until asuitable wet mass was formed (ranging from approximately 3 to 14 mins)at 420 rpm. The resultant granules were dried to appropriate moisturecontent (≤2% LOD) using a fluid bed dryer (Aeromatic Strea 1) with aninlet air temperature of 80° C. The dried granules were milled using anappropriately sized screen (1.4 mm, Quadro Comil U3). SSF was then addedto the granules, which were then blended (Copley, Mobile Blender 7.5liter drum) for 5 mins at 25 rpm before compressing into tablet coresusing conventional tabletting equipment (Korch XL 100).

Dissolution was determined according to the general procedure of theUnited States Pharmacopeia using Apparatus 2 with pH1.3 hydrochloricacid and sodium chloride buffered solution at 37° C.±0.5° C. and stirrerspeed of 50 rpm. At 15, 30 and 60 minutes dissolution media waswithdrawn and the concentration of Formula (I) in solution wasdetermined by UV spectroscopy at a wavelength of 311 nm against anexternal standard solution. Dissolution profiles are shown in FIG. 2,the dissolution data is presented in Table 10.

TABLE 10 Run 15 minutes 30 minutes 60 minutes 1 82.6 91.3 91.8 2 68.978.6 89.2 4 67.5 77 86.3 5 101.1 100.7 100.2 6 91.7 97.8 99.8 7 96.9 9797.5 8 61.8 73.9 89.9 9 107.2 106.9 107.9 10 54.5 69.4 84.9 11 98.6 93.698 12 92.9 97.9 101.3 13 104.3 108.7 112.8 14 106.3 108.1 108.5 15 101.1100.8 101.1 16 100 99.5 100.4 17 97.5 99.9 101.3 18 97.9 88.7 98.3 19 8694.5 100.4

Example 5: Assessment of Chemical Stability of a Sixteen AlternativeTablet Forms

Sixteen different prototype tablets were prepared from a wet granulationformulation using methods well known to those skilled in the art. Thecomposition and manufacturing process of each of these tablets isdescribed in Table 11.

TABLE 11 Second- Run Main ary Sur- Order Filler Filler DisintegrantBinder factant Lubricant 1 Mannitol DCPA L-HPC HPC None SSF 2 MannitolDCPD SSG HPC None SSF 3 Mannitol DCPD L-HPC HPC SLS MgST 4 Mannitol DCPASSG HPMC SLS SSF 5 Mannitol DCPA L-HPC HPMC None MgST 6 MCC DCPA SSGHPMC None SSF 7 MCC DCPA L-HPC HPC SLS SSF 8 Mannitol DCPD L-HPC HPMCSLS SSF 9 MCC DCPD L-HPC HPMC None SSF 10 MCC DCPA L-HPC HPMC SLS MgST11 MCC DCPA SSG HPC None MgST 12 MCC DCPD L-HPC HPC None MgST 13Mannitol DCPA SSG HPC SLS MgST 14 Mannitol DCPD SSG HPMC None MgST 15MCC DCPD SSG HPMC SLS MgST 16 MCC DCPD SSG HPC SLS SSF

Formula (I) and the excipients (except lubricant) described in Table 11(total batch size approximately 50 g) were charged to a mixer-granulator(Mi-Pro, 500 ml bowl) and mixed. Purified water was added (approximately10 ml/min) to the powders with further mixing until a suitable wet masswas formed. The resultant granules were dried to appropriate moisturecontent (≤2% w/w LOD) using a fluid bed dryer (Vector, MF1.01). Thedried granules were milled using an appropriately sized screen (1 mm,Quadro Comil U3). Lubricant was then added to the granules, which werethen blended (WAB turbula) for 4 mins at 24 rpm before compressing intotablet cores using conventional tab letting equipment (Manesty F3 tabletpress).

Total impurities were measured by injection of the prepared sample andstandard solutions onto an LC system selected to ensure the separationof Formula (I) from organic impurities and excipients. Thechromatographic responses due to Formula (I) and organic impurities aremeasured on a UV detector at wavelength 245 nm. The response due toFormula (I) present in the sample was compared to that of a standard andits assay was calculated. The level of organic impurities was calculatedas % w/w. Equivalent response was assumed between Formula (I) andorganic impurities,

Samples were stored in a controlled environment for four weeks at 60° C.and 80% relative humidity. After analysis, samples with SSF in theircomposition contained 0.99±0.36% (mean±standard deviation %) and sampleswith MgSt in their composition contained 1.93±1.34% (mean±standarddeviation %).

Example 6: Assessment of Dissolution Performance when Varying SSFConcentration and Inclusion of an Alternative Lubricant

Full extent of release was not achieved for each of the prototypeformulations presented in Example 4 in pH 6.8 phosphate bufferedsolution. The affect of lubricant was investigated and five differentprototype tablets were prepared by a wet granulation process usingmethods well known to those skilled in the art. The composition of eachof these tablets is described in Table 12.

TABLE 12 Milled granules from composition variant SSF Glydb Run (Table5) (% w/w) (% w/w) 0% SSF 17 and 18 0.0 N/A 1% SSF 17 and 18 1.0 N/A 2%SSF 17 and 18 2.0 N/A 5% SSF 17 and 18 5.0 N/A 3% Glybd 17 and 18 N/A3.0

Milled unlubricated granules from the prototype variants 17 and 18(equivalent compositions), presented in example 4 (Table 9), werecombined with the relevant level of lubricant, presented in Table 12,and blended (WAB turbula) for 5 mins at 25 rpm before compressing intotablet cores using conventional tabletting equipment (RIVA mini-press).Dissolution was determined according to the general procedure of theUnited States Pharmacopeia using Apparatus 2 with pH6.8 phosphatebuffered solution at 37° C.±0.5° C. and stirrer speed of 75 rpm. At 15,30, 45 and 60 minutes dissolution media was withdrawn and theconcentration of Formula (I) in solution was determined by UVspectroscopy at a wavelength of 298 nm against an external standardsolution. Dissolution results are shown in FIG. 3 and the dissolutiondata is presented in Table 13.

TABLE 13 Run 15 minutes 30 minutes 45 minutes 60 minutes 0% SSF 85 94 9799 1% SSF 83 91 94 96 2% SSF 74 81 86 89 5% SSF 65 71 74 76 3% Glybd 8393 97 99

Example 7: Assessment of Tablets of Formula (I) Prepared with DifferentLubricants

Three different prototype tablets were prepared from a wet granulationformulation using methods well known to those skilled in the art. Thecomposition of each of these tablets (including a range of lubricantsi.e. MgSt, SSF and Glydb) is described below. The pharmaceuticalcomposition comprises the following components (% w/w):

Composition A Composition B Composition C (% w/w) (% w/w) (% w/w) APIFormula 10.0 Formula 21.3 Formula 21.3 (I) (I) (I) Primary FillerMannitol 60.0 Mannitol 31.2 Mannitol 31.2 Secondary DCPD 20.0 MCC 15.0MCC 15.0 Filler Tertiary Filler MgCO₃ 20.0 MgCO₃ 20.0 Disintegrant SSG5.0 SSG 7.5 SSG 7.5 Binder HPMC 4.0 HPC 2.0 HPC 2.0 Lubricant MgSt 1.0SSF 3.0 Glydb 3.0Manufacturing processes for Compositions A, B and C are given in Example5, Example 4 and Example 6, respectively.

An evaluation of tablet dissolution performance was made (Table 14).Dissolution was determined according to the general procedure of theUnited States Pharmacopeia using Apparatus 2 with pH6.8 phosphatebuffered solution at 37° C.±0.5° C. and stirrer speed of 50 rpm. At 15,30, and 60 minutes dissolution media was withdrawn and the concentrationof Formula (I) in solution was determined by UV spectroscopy at awavelength of 298 nm against an external standard solution.

TABLE 14 Composition 15 minutes 30 minutes 60 minutes A 55.8 82.5 88.3 B69.3 76.3 78.1 C 79.0 88.2 93.7

Composition C was selected for further study because, unlike othercompositions, it (i) did not contain MgSt, which on average gave moreimpurities than SSF (Example 5); (ii) did not contain SSF, inclusion ofwhich can affect extent of dissolution release (FIG. 3); and (iii),demonstrated acceptable dissolution performance throughout thephysiologically relevant pH range (Table 15).

TABLE 15 Composition C 15 minutes 30 minutes 60 minutes pH 1.3 98.2101.5 102.0 pH 6.8 79.0 88.2 93.7

Example 8: Assessment of Dissolution Performance of Ten AlternativeTablet Formulations

Ten alternative prototype tablets were prepared from a wet granulationusing methods well known to those skilled in the art. The composition ofeach of these tablets is qualitatively similar to Composition C (Example7). Quantitative compositions are set out in Table 16.

TABLE 16 API (% MgCO3 Glydb Mannitol MCC SSG HPC Composition w/w) (%w/w) (% w/w) (% w/w) (% w/w) (% w/w) (% w/w) 1 10 15 8 38.72 18.78 7.5 22 40 25 8 11.67 5.83 7.5 2 3 10 25 1 36.79 17.71 7.5 2 4 40 15 1 23.2911.21 7.5 2 5 40 25 8 11.67 5.83 7.5 2 6 10 15 1 43.55 20.95 7.5 2 7 4025 1 16.54 7.96 7.5 2 8 10 25 8 31.67 15.83 7.5 2 9 21.33 20 3 31.17 157.5 2 10 21.33 20 3 31.17 15 7.5 2

Formula (I) and the excipients (except lubricant) described in Table 16(total batch size approximately 250 g) were charged to amixer-granulator (Diosna, 1 liter bowl, P1/6) and mixed. Purified waterwas added (approximately 10 ml/min) to the powders with further mixinguntil a suitable wet mass was formed. The resultant granules were driedto appropriate moisture content (≤2% w/w LOD) using a fluid bed dryer(Aeromatic Strea 1). The dried granules were milled using anappropriately sized screen (1.4 mm, Quadro Comil U3). Lubricant was thenadded to the granules, which were then blended (WAB turbula) for 10 minsat 55 rpm. The granules were then compressed into tablet cores (eachcore normalised to 80 mg of formula 1) using conventional tablettingequipment (Riva Piccola (W.I.P) tablet press) at a normalised pressureof 100 MPa.

An evaluation of tablet dissolution performance was made (Table 17 and18). Dissolution was determined according to the general procedure ofthe United States Pharmacopeia using Apparatus 2 with both pH6.8phosphate solution and pH1.3 hydrochloric acid and sodium chloridesolution at 37° C.±0.5° C. and stirrer speed of 50 rpm. At 15, 30, and60 minutes dissolution media was withdrawn and the concentration ofFormula (I) in solution was determined by UV spectroscopy at awavelength of 311 nm (for pH 1.3 solution) or 298 nm (for pH 6.8solution) against an external standard solution. Dissolution results areshown in Table 17/FIG. 4 (pH 1.3) and Table 18/FIG. 5 (pH 6.8).

TABLE 17 Composition 15 minutes 30 minutes 60 minutes 1 104 102 102 2 8490 93 3 95 94 94 4 72 79 87 5 78 90 95 6 111 110 110 7 91 93 95 8 100 9898 9 98 97 98 10 96 95 96

TABLE 18 Composition 15 minutes 30 minutes 60 minutes 1 67 86 97 2 38 5673 3 55 72 84 4 38 58 77 5 36 54 72 6 83 98 105 7 56 75 87 8 71 86 93 956 77 91 10 47 68 84

Example 9: Assessment of Tablet Punch Filming Often Alternative TabletFormulations

Ten alternative prototype tablets were prepared from a wet granulationformulation using methods well known to those skilled in the art. Thecomposition and manufacturing process of each of these tablets isdescribed in Example 8.

Material adhesion to tablet punch surfaces (described below as‘filming’) is a well known tabletting process defect (Journal ofPharmaceutical Sciences, Vol. 93(2), 2004). Extent of filming wasvisually assessed for each formulation and reported in Table 19.

TABLE 19 Composition Filming 1 No filming 2 No filming 3 ★★ 4 ★★ 5 Nofilming 6 ★★ 7 ★★★ 8 No filming 9 No filming 10 No filming ★ = minor ★★= moderate ★★★ = severe

No punch filming was observed for the compositions with 3-8% w/w glydb.Moderate to severe levels of punch filming was observed for thecompositions containing 1% w/w glydb under the process conditionsapplied.

Example 11: Assessment of Dissolution of an Alternative TabletFormulation

One alternative tablet formulation was prepared from a wet granulationusing methods well known to those skilled in the art. The composition ofthe tablet core is quantitatively similar to Composition C (Example 7)and a film coat was applied using a conventional film coating method toenhance the tablet appearance. The quantitative composition of thetablet core formulation is presented in Table 20.

TABLE 20 Component Composition (% w/w) AZD4547 21.33 Mannitol 31.17Micro crystaline cellulose 15 (Avicel PH101) Magnesium Carbonate 20(Heavy) Sodium Starch Glycolate 7.5 Hydroxy Propyl Cellulose 2 Glyceryldibehenate 3

A film coat was applied using a propriety mixture of coating excipients,Opadry II Biege, supplied by Colorcon.

Formula (I) and the excipients (except lubricant) described in Table 20(total batch size approximately 5 kg) were charged to a mixer-granulator(Gral 25) and mixed. Purified water was added (approximately 166 ml/min)to the powders with further mixing until a suitable wet mass was formed.The resultant granules were dried to appropriate moisture content (≤2%w/w LOD) using a fluid bed dryer (Glatt 59P). The dried granules weremilled using an appropriately sized screen (1.4 mm, Quadro Comil U3).Lubricant was then added to the granules, which were then blended(Copley Mobile Blender, 7.5 L container) for 5 mins at 25 rpm. Thegranules were then compressed into tablet cores using conventionaltabletting equipment (Riva Piccola-Nova, tablet press) to achieve atarget compression weight of 375 mg. The tablet cores were over coatedwith a film coat using conventional pan coating equipment (O'HaraLabcoat II-X) to achieve a tablet weight gain of 3% w/w.

An evaluation of tablet dissolution performance was made (Table 22).Dissolution was determined according to the general procedure of theUnited States Pharmacopeia using Apparatus 2 with both pH6.8 phosphatesolution and pH1.3 hydrochloric acid and sodium chloride solution at 37°C.±0.5° C. and stirrer speed of 50 rpm. At 15, 30 and 60 minutesdissolution media was withdrawn and the concentration of Formula (I) insolution was determined by UV spectroscopy at a wavelength of 311 nm(for pH 1.3 solution) or 298 nm (for pH 6.8 solution) against anexternal standard solution.

TABLE 22 15 minutes 30 minutes 60 minutes pH 1.3 95 101 103 pH 6.8 75 8793

The invention claimed is:
 1. A pharmaceutical composition comprising 15%w/w to 25% w/w of the compound of Formula (I):

and 15% w/w to 25% w/w of an alkaline effervescent agent that issufficient to provide satisfactory in vitro dissolution at a pH wherethe compound of Formula (I) is no more than slightly soluble, whereinthe effervescent agent is magnesium carbonate; wherein the compositioncomprises between 0.25% w/w and 8% w/w of an alternative lubricant;wherein the alternative lubricant is glyceryl dibehenate; and furthercomprising one or more pharmaceutically acceptable ingredients.
 2. Apharmaceutical composition according to claim 1 wherein the compositioncomprises between 2.5% w/w and 3.5% w/w of the alternative lubricant. 3.A pharmaceutical composition according to claim 1, wherein the in vitrodissolution is greater than or equal to 70% dissolution of the compoundof Formula (I) within 30 minutes at pH 1.3.
 4. A pharmaceuticalcomposition comprising: (a) 15% w/w to 25% w/w of a pharmaceuticallyactive compound, wherein the pharmaceutically active compound consistsof the compound of Formula (I):

and (b) 15% w/w to 25% w/w of an alkaline effervescent agent that issufficient to provide satisfactory in vitro dissolution, wherein theeffervescent agent is magnesium carbonate; wherein the compositioncomprises between 0.25% w/w and 8% w/w of an alternative lubricant;wherein the alternative lubricant is glyceryl dibehenate; and (c)further comprising one or more pharmaceutically acceptable ingredients.